ABSTRACT On planet earth, organisms have evolved mechanisms to synchronize metabolic and physiological functions with the ~24 hour light/dark cycle. Interestingly, many human diseases have associations with the circadian day. When traveling across time zones, our sleep-wake patterns, mental alertness, eating habits and many other physiological processes temporarily suffer the consequences of being ?out of phase? until we adjust to the new time zone. In addition, a significant portion of the population works the ?graveyard? shift, including health care workers, police officers, truck drivers and factory workers. Recent studies have linked disruption of the circadian clock with numerous ailments, including: asthma, cancer, metabolic syndrome, cardiovascular diseases, psychiatric diseases, and learning disorders. Tremendous knowledge has come from studying the genetic and molecular basis of circadian rhythms in model organisms. Despite the importance of the circadian clock to all aspects of our physiology and behavior, the opportunity to probe the human circadian clock only became possible with the recognition of Mendelian circadian variants in people (familial advanced sleep-phase, FASP). We characterized FASP, collected many families, and mapped and cloned the first FASP genes. We went on to identify a total of 6 FASP genes and have generated animal models of all of them. Still, a large majority of FASP families do not have mutations in the known clock genes. In this proposal, we outline a plan to continue collecting additional families (Aim 1), to perform whole exome sequencing in probands from >50 ?unexplained? FASP families, and to sift among the variants to identify novel circadian rhythm/FASP genes/mutations (Aim 2). Finally, since the first 1-2 years will be focused on identifying novel FASP genes, we propose to perform in vitro and in vivo studies of a human FASP mutation in the TIMELESS gene (Aim 3). Parallel studies in humans and mouse models will synergize in dissecting understanding of FASP in humans and exploring the similarities and differences between our circadian clocks vs. those of other organisms. Studying the molecular mechanism of human circadian rhythmicity will have an enormous impact on our understanding of human health & disease. It should also lead to new strategies for pharmacological manipulation of the human clock to improve the treatment of jet-lag, various clock-related sleep and psychiatric disorders, as well as other human diseases. Understanding of the human clock genes and mutations will enable development of better therapies for ASPS of aging, jet lag, and other sleep disorders.